Carbamyl-pyrazolidin-3, 5-diones



United States Patent 3,174,976 CARBAMYL-PYRAZOLIDlN-lS-DIGNES Donald P. Cameron, New London, Conrr, assignor to Chas. Pfizer & (10., Inc, New York, N.Y., a corporation of Delaware No Drawing. Filed Mar. 21, 1962, Ser. No. 181,459 9 Claims. (Cl. Zed-41d} The present invention is concerned with new amides of the pyrazolidin-dione series, and salts thereof, as well as the production of these compounds; the new compounds have valuable pharmacological properties.

It has been found that the new 4-carbamyl-L2-diarylpyrazolidin-3,5-diones and their salts exhibit excellent anti-pyretic, analgesic and anti-inflammatory activity.

The new compounds have the following general formula:

wherein R and R are each selected from the group consisting of .aryl, hetero-aryl, alicyclic, hetero-interrupted-alicyclic, lower alkyl, lower alkoxy carbonyl, carbamyl, lower alkyl car boxamido and phenyl carbarnyl;

R and R are each selected from the group consisting of alkyl, phenyl, substituted phenyl, heteroaryl and, when taken together with the geminal carbon atom, cycloalkyl and hetero-interrupted alkyl and R represents hydrogen or lower alkyl.

A preferred class of compounds are those of the above structural formula wherein R and R are selected from the group consisting of phenyl, halophenyl, hydroxyphenyl, lower alkoxy phenyl, carbo lower alkoxy phenyl; said lower alkoxy radicals having up to 3 carbon atoms, lower alkyl mercapto phenyl, lower alkyl phenyl, said alkyl radicals having up to 5 carbon atoms, trifluoromethyl phenyl, pyridyl, thienyl and thiazolyl;

R and R are each selected from the group consisting of lower alkyl, phenyl, lower alkoxy pheny-l, said lower alkoxy radicals having up to 3 carbon atoms, lower alkyl mercapto phenyl, lower alkyl phenyl, said alkyl radicals having up to 5 carbon atoms, pyridyl, thienyl, thiazolyl, and when taken together with the geminal carbon atom, cycloheptyl, cyclohexyl, cyclopentyl, cyclobutyl and lower alkyl-substituted cycloalkyls of this type, as well as piperidyl and N-alkyl piperidyl and R is selected from the group comprising hydrogen and alkyl, said alkyl radicals having up to 5 carbon atoms.

A particularly valuable group are those compounds of the generic formula ice and the pharmaceutically acceptable salts thereof, wherein R is selected from the group consisting of phenyl and parahydroxyphenyl,

R when taken separately is selected from the group consisting of alkyl of up to 4 carbon atoms, pyridyl, thienyl, thiazolyl, phenyl and mono-substituted phenyl, wherein said substituent is selected from the group consisting of hydroxy, alkoxy of up to 3 carbon atoms and alkyl and alkyl mercapto of up to 5 carbon atoms,

R when taken separately is selected from the group consisting of methyl, and ethyl, provided that R is methyl when R is alkyl,

R and R when taken together with the quaternary carbon atom to which they are attached form a cyclic substituent selected from the group consisting of cyclobutyl, cyclopentyl, monoalkyl cyclopentyl, cyclohexyl, monoalkyl, cyclohexyl, cycloheptyl, piperidyl and N-alkyl piperidyl, each of said alkyl substituents having up to two carbon atoms, and

R is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-prop-yl, n-butyl, i-butyl, s butyl and t butyl.

The compounds of the present invention in which R defined above is hydrogen may be formed according to the reaction illustrated by the following chemical equation:

wherein R, R R and R have the meanings given above.

Although the ratio of reactants is not critical, it is preferred to carry out the reaction with a mol-ratio of water to nitrile in eXcess o-f 1.0 and to use a substantial excess of to percent sulfuric acid. A particularly effective concentration has been found to be about ml. of 9095 percent sulfuric acid per 0.1 mol of nit-rile. The time and temperature of the reaction varies somewhat depending upon the nitrile used. However, it has been found that temperatures in the range of about 80 to about 120 C. and times of order of about 5 minutes to about one hour are sufiicient. The product is precipitated by the addition of about 10 to 20 volumes of ice-water to the reaction mixture and the precipitate is purified by recrystallization from an organic solvent such as a lower alkanol, ethyl acetate, acetone, and the like.

In a particularly convenient modification of the above procedure for preparation of compounds of the instant invention, wherein R as defined above is hydrogen, the nitrile is dissolved in a mixture of absolute ethanol and concentrated sulfuric acid, the reaction mixture is heated and refluxed at temperatures up to about 120 degrees C. and, after a reaction period which can vary from about 5 minutes to about 3 hours, the solution is poured into about 10 to 20 volumes of ice-water. The product is precipitated thereby and can be further purified as by recrystallization.

The compounds of the present invention wherein R as defined above comprises lower alkyl of one to 5 carbon atoms and wherein said lower alkyl groups may be straight or branched can be formed according to the general reaction illustrated by the following equations:

RNC\/\H R2 (Le-R1 (molar;

R4N-C\ N R4-N-C ONHRa 0 wherein R, R R and R have the meanings given above.

Although the ratio of the boron trifluoride-etherate complex to the nitrile reactant to be employed is not critical, it is preferred to use a molar excess of the complex of about 2- to about 3-fold to overcome the tendency of a possible O-alkylation side reaction to occur. For the second step, while not critical, it is preferred to use a 2.0 mol-ratio of water to nitrile. The first step can be carried out at temperatures of about 20 to about 100 degrees C., but it is preferred to carry it out at about 50 to about 70 degrees C. and for such time as is necessary for the reaction mixture to become homogeneous (usually less than one hour). It is preferred to carry the second reaction out at reflux temperatures for about 1 to about 5 hours after which time about to volumes of icewater is added and the product is extracted with an organic solvent. The organic extract is dried and filtered, then the solvent is evaporated and the carbamyl-pyrazolidin-3,5-dione can be further purified, as by recrystallization from a lower alkanol or from ethyl acetate.

The compounds of instant invention in which R as defined above comprises branched lower alkyl of 3 to 5 carbon atoms can be formed according to the reaction illustrated by the following chemical equations:

wherein R, R R and R are defined as above, and wherein a is a methyl and b, c and d are hydrogen when R is to contain 3 carbon atoms; wherein a and c are methyl and b and d are hydrogen; or a and b are methyl and c and d are hydrogen; or a is ethyl and b, c and d are hydrogen when R is to contain 4 carbon atoms; and wherein a is n-propyl and b, c and d are hydrogen; or a is i-propyl and b, c and d are hydrogen; or a is ethyl, b is methyl and c and d are hydrogen; or a is ethyl, c is methyl and b and d are hydrogen; or a, b and c are methyl and d is hydrogen when R is to contain 5 carbon atoms.-

CIl

Compounds contemplated by the present invention in which R as defined above is t-butyl can also be conveniently prepared with t-butanol substituted for isobutylene in the reaction above. In this case, under the conditions of the reaction, t-butanol is converted to isobutylene which reacts in the manner described.

Although the ratio of the reactants is not critical, it has been found that the use of at least equimolar quantities of alkene or tertiary carbinol gives good yields and an excess is to be preferred The time and temperature for this reaction will vary somewhat depending upon the nature of the reactants. However, the desired N-alkylcarbamyl derivative is formed if the reaction is carried out at temperatures from about 20 to about degrees C. for periods of about 0.5 hour to about 72 hours. It has been found particularly convenient to carry out the reaction at about 70 degrees C. for 1 hour, then to lower the temperature to 25 C. for an additional 24 to 72 hours. It has also been found somewhat advantageous to add about 1 to about 5 percent sulfur trioxide in order to insure anhydrous reaction conditions. The product is precipitated by the addition of ice-water and, after filtration, it is further purified by recrystallization from a lower alkanol such as, for example, methanol, ethanol, isopropanol, and the like.

While the procedures described are preferred, it is to be understood that other methods known to the art can be used to form the compounds of instant invention. Some difficulty has been found, however, in attempts to prepare the corresponding carboxylic acids from 4-(1- cyano)alkylpyrazolidin-B,S-diones. These acids, which are of potential use as intermediates in the synthesis of the compounds of the present invention, are not readily formed by hydrolysis reactions; rather, there is a tendency for the pyrazolidindione ring to be cleaved instead.

The nitrile starting materials used in preparation of compounds of instant invention can readily be prepared by the procedures outlined in the following reactions:

pares with 10 to 30 percent with phenyl butazone; each compound was administered at a dosage of 70 mg./ kg.

In addition, compounds of the instant invention are effective analgesics. They compare favorably with aspirin in this respect. Particularly effective is 1,2-diphenyl-4-- 1'-carbamyl-1'-methyl)ethylpyrazolidin-3,S-dione.

In certain cases, it may be found that absorption of the compound into the system is poor due to low solubility; in water. Since the new compounds are acidic, absorp-- tion may usually be increased by administering them in the form of pharmaceutically-acceptable sa1ts, i.e., those formed by reaction with inorganic or organic bases which do not substantially increase the toxicity of the active agents.

Suitable bases for the preparation of pharmaceutically acceptable salts includes the hydroxides, carbonates and bicarbonates of the alkali metals, sodium and potassium, and of alkaline earth metals of atomic number up to and including 20, i.e., magnesium and calcium, as well as ammonium, aluminum, zinc, iron and manganese, among others; and additionally organic bases of adequate strength such as dibenzylethylenediamine and such water-soluble amines as the lower alkanolamines including ethanolamine and the like.

Of course, the phamaceutically-unacceptable salts, while not suitable for therapy, are useful for isolation and purification of the new compounds, as well as for preparation of the pharmaceutically acceptable salts. Pharmaceutically-unacceptable salts include, most commonly, salts of lithium and of alkaline earth metals of atomic number greater than 20, i.e., barium and strontium.

The salts may be prepared by treating the new products of the present invention in solution with an equimolar proportion, or a slight excess, of the chosen base. In the case of the water-soluble bases, the active agents may be treated in a water-miscible solvent such as dimethoxyethane with a water solution of the base. The more insoluble salts precipitate immediately and may be recovered by filtration, while others will crystallize upon partial evaporation of the solvent, or addition of a nonsolvent. The most soluble salts may be recovered by evaporation to dryness followed by washing of the residue with .a non-solvent such as alcohol.

The following examples illustrate the present invention and are not to be construed as limitations thereof. It is apparent from the preceding description and the appended claims that many variations of the examples are possible without departing from the spirit or scope of the invention.

EXAMPLE I 1 ,Z-dipheny [-4-(] -methyl-] 'cyano) ethyl pyrazolidin- 3 ,5 -di0ne Ten ml. of acetone (approximately 7.9 grams) are added to 0.1 mol of 1,Z-diphenyl-pyrazolidin-3,5-dione. The mixture is stirred and then heated to 50 degrees C. for 2 hours. The desired alkylidene intermediate is obtained by distilling off the solvent in vacuo. The dried residue is washed with 100 ml. of 2 percent Na CO and then with two 100 ml. portions of water. The resultant product is recrystallized from ethyl alcohol.

In a modification of the preceding reaction, the dione compound is added directly to 200 ml. of acetone. The acetone thus is used both as a reactant and as a solvent. By employing the same reaction conditions set forth above, substantially identical results are obtained.

To 0.05 mol of the alkylidene product of the preceding sections, a aqueous solution of sodium cyanide is slowly added at room temperature with stirring until the characteristic color of the alkylidene compound is no longer discernible.

The reaction mixture is extracted with an equal volume of chloroform. After this extraction step has been repeated twice more, the aqueous layer is acidified with 1.0 N HCl. A precipitate appears when the pH has been adjusted to approximately pH 3. The precipitate is separated by filtration and then recrystallized from 95 percent isopropyl alcohol to obtain the desired 1,2-dipheny1- 4-(1'-methyl-l'-cyano)ethyl-pyrazolidin-3,5-dione:

melting point 176-177 C.

6 EXAMPLE 11 Following the procedure of Example I, the nitriles tabulated below are prepared from the appropriate ketones.

O C aH5-NO\H Rz 1-( /'Rl C H N-O (5N phenyl methyl o-hydroxyphenyl methyl p-hydroxyphenyl methyl o-methoxyphenyl ethyl -CH2CH2CH2- CHzCHzCHaCHz- CH1CH(OH3)CH2CH2 -CHzCH2CHgCHqCI-Iz -CHzCHzCHzCHzCHzCHz- CHZCH(CH3) CHzOHgCHz- -CH;CHCH(CH3) CHzCH -CHzCHzN (CH3) CHzCH-z p-methylphenyl methyl 2-pyridyl ethyl i-propyl methyl n-butyl methyl i-butyl methyl 2-thienyl methyl 5-thiazolyl methyl m-propylphenyl methyl p-amylphenyl methyl p-methylmercaptophenyl ethyl m-amymercaptophenyl methyl p-propoxyphenyl methyl --CHgGH(CqH5)CHzClI2- -CH CH;CH(C2H CH:CH2 CH2CHzNHCHzCH2- --CH2N(C:H,5) CHgCHzCHzs-butyl methyl EXAMPLE III 1- (p-hydroxyphenyl) -2-phenyl-4-(1-cyan0)-cycl0hexylpyraz0lidin-3,5-di0ne 15.5 grams of l-(p-acetoxyphenyl)-2-phenylpyrazolidin- 3,5-dione and 7.0 g. of cyclohexanone in 50 ml. of acetic acid containing 0.4 g. of ammonium acetate and 2.0 g. of acetic anhydride are heated for 3.5 hours under nitrogen at a temperature of -115 degrees C. The mixture is then permitted to stand at room temperature for 12 hours. The acetic acid is distilled 01f under vacuum and the residue is crystallized from ethanol. The intermediate weighs 15.65 g. and has a melting point of 131-133 degrees C. After several recrystallizations, it melts at 131- 135 degrees C. and exhibits the following analysis:

Percent Carbon 70.75 Hydrogen 5.68 Nitrogen 7.8

15.0 grams of the condensation product of l-(p-acetoxyphenyl)-2-phenylpyrazolidin-3,S-dione and cyclohexanone is now dissolved in 100 ml. of dioxane. This solution is added dropwise to a solution of 5.64 g. of sodium cyanide in 75 m1. of water at 0 to 5 degrees C. The mixture is stirred under nitrogen. During addition, a light yellow precipitate forms. After stirring an hour and a half, the solution becomes clear. It is permitted to stand at room temperature for 16 hours, and 100 ml. of water is added. The solution is extracted with methylene dichloride using 4 ml. portions. The aqueous solution is now acidified at a temperature of 0 to 5 degrees C., using 35 ml. of 10 percent hydrochloric acid and adjusting the mixture to a pH of 2. After stirring for one hour under nitrogen, the mixture is filtered. The product is washed with water and the light pink solid is dried at room temperature. It Weighs 14.15 g. and has a melting point of 183-187 degrees C. After recrystallization from isopropanol and methylene chloride, it melts at 185-187 degrees C. During the process, the acetoxy group has been hydrolyzed.

7 Thus, the product is l-(p-hydrcxyphenyl)-2-phenyl-4-(1'- cyano)-cyclohexylpyrazolidin-3,S-dione.

EXAMPLE IV Following procedure of Example 111 the products tabulated below are prepared from 1(p-acetoxyphenyl)-2- phenylpyrazolidine-3,S-dione and the appropriate ketones:

EXAMPLE V Preparazian. f 1,2-diphenyl-4-(1 -carbamyl1 -meihyl) ethylpyraz0lidin-3,5-di0ne To 150 ml. of 96 percent sulfuric acid heated to 90 degrees C. is added 0.1 mol of 1,2-diphenyl-4-(1-cyano-1- methyl)ethylpyrazolidin-3,S-dione. The reaction temperature rises spontaneously to 108 degrees and the mixture is stirred for a total of 12 minutes. The mixture is .1 treated with 2 liters of ice water and stirred for one-half hour. The White, crystalline precipitate which is formed is extracted into 2.5 liters of methylene chloride, the organic extract is separated, washed with 0.5 liters of water and then extracted with two 0.5-liter portions of 0.4 N sodium hydroxide. The sodium hydroxide extract is separated, washed with methylene chloride, treated with a small amount of carbon, filtered, cooled to 5 degrees C. and acidified with 250 m1. of concentrated hydrochloric acid. The resulting white crystalline product is isolated by extraction into 2.5 liters of methylene chloride, the separated extract is washed twice with 0.5 liter of water, then is dried over magnesium sulfate, filtered and concentrated in vacuo to a volume of 0.2 liters. A crystalline precipitate separates from the cooled concentrate. This weighs 22 grams and melts with decomposition at 187- 188 C. After recrystallization from ethyl acetate, 1,2- diphenyl 4 (1 carbamyl 1' methyl)ethylpyrazolidin-3,5-dione is obtained having a melting point of 188- 189 C.

Analysis.-Calcd.: C, 67.64; H, 5.68; N, 12.46. Found: C, 67.51; H, 5.71; N, 12.63.

An ultraviolet absorption maximum is observed at 241 m (E %=460) in 0.01 N HCl-methanol.

When the described reaction is repeated substituting 1,2 diphenyl 4 (1 cyano 1' methyl)propylpyrazolidin-3,5-dione for the corresponding nitrile, there is obtained 1,2-diphenyl-4-(1-carbamyl-1'-methyl)propylpyrazolidin-3,5-dione.

EXAMPLE VI Preparation 0 1,2-diphenyl-4-(I'-carbamyl-4-methyl)- cyclohexylpyraz0lidin-3,5-di0ne 1,2 diphenyl 4 (1 cyano 4' methyl)cyclohexyl .pyrazolidin-3,5-dione, 3.5 g., 0.01 mol is dissolved into a solution of 15ml. of concentrated sulfuric acid in 200 ml. of absolute ethyl alcohol at 96 degrees C. The reaction temperature rises spontaneously to 118 degrees C. in 2 minutes and after 5 additional minutes during which the temperature decreases to 97 degrees, the reaction mixture is treated with 200 ml. of ice-water. The crystalline product is isolated by filtration and is recrystallized from ethyl acetate. There is obtained 2.0 g. of 1,2-dipheny1-4-(1- carbamyl 4' ethyl)cyclohexylpyrazolidin 3,5 dione having a melting point of 215-216 degrees C.

Analysis.-Calcd.: C, 70.6; H, 6.4; N, 10.7. Found: C, 70.64; H, 6.13; N, 10.83.

Ultraviolet absorption maxima are observed at 241 mn (E =413) in 0.01 N HCl-methanol, and at 265 mp (E =595) in NaOH.

When the described reaction is repeated substituting 1,2 diphenyl 4 (1 cyano)cyclohexylpyrazolidin- 3,5-dione for the corresponding nitrile, there is obtained 1,2 diphenyl 4 (1 carbamyl)cyclohexylpyrazolidin-3,5-dione, melting at 222-223 degrees C.

Analysis.Calcd.: C, 70.1; H, 6.14; N, 11.13. Found: C, 70.12; H, 6.02; N, 11.30.

Ultraviolet absorption maxima are observed at 243 mp. (E =390) in 0.01 N HCl-methanol, and at 265 m (E =598) in NaOH.

When the described reaction is repeated substituting 1,2- diphenyl 4 (1' cyano)cyclopentylpyrazolidin 3,5- dione for the corresponding nitrile, there is obtained 1,2- diphenyl 4 (1 carbamyl)cyclopentylpyrazolidin 3,5- dione, melting at 219-220 degrees C.

Analysis.-Calcd.: C, 69.4; H, 5.83; N, 11.56. Found: C, 69.39; H, 5.80; N, 11.62.

An ultraviolet absorption maximum is observed in 0.01 N HCl at 241 mp (E =454).

When the above described reaction is repeated substituting 1,2-dipheny1-4-( 1'-cyano-3 -methyl) eyclopentylpyrazolidin-3,5-dione for the corresponding nitrile, there is obtained 1,2-diphenyl-4- 1'-carbamyl-3-methyl)cyclopentyl pyraz0lidin-3,5-dione, melting at 192-193 degrees C.

Analysis.Calcd.: C, 70.0; H, 6.1; N, 11.1. Found: C, 70.34; H, 6.13; N, 11.13.

An ultraviolet absorption maximum is observed in 0.01 N HCl at 242 m (E =414).

EXAMPLE VII Preparation of 1,2-diphenyl-4-(1 -N-ethylcarbamyl-1 methyl)ethylpyrazolidin-iS-dione 1,2 diphenyl 4 (1 cyano 1 methyl)ethylpyrazolidin-3,5-dione, 3.2 g., 0.01 mol is dissolved in 60 ml. of warm boron trifluoride-diethyl etherate during 15 minutes, then 0.02 mol, 0.36 g. of water is added. The reaction mixture is refluxed for one hour during which a white precipitate forms and after an additionl 5 hours, 200 grams of ice-water is added. The oil which separates is extracted with methylene chloride, the extract is dried over magnesium sulfate and the methylene'chloride is removed by distillation in vacuo. A glassy residue is obtained which after recrystallization from isopropanol has a melting point of 174-176 degrees. A second recrystallization from isopropanol yields 1,2-dipheny1-4-(l'-N- ethylcarbamyl-1-methyl)ethylpyrazolidin-3,5-dione, melting at 1805-1815 degrees C.

Analysis.Ca1cd.: C, 69.02; H, 6.34; N, 11.50. Found: C, 69.18; H, 6.28; N, 11.48.

An ultraviolet absorption maximum is observed in 0.01 N HCl at 241 m (E z,=436).

ml. of glacial acetic acid and treated with 6 m1. of concentrated sulfuric acid and 6 ml. of tert.-butyl alcohol.

One ml. of sulfur trioxide is added to insure anhydrous conditions. The reaction mixture is heated at 70 degrees C. for one hour, then is held at degrees C. for 72 hours, and then is treated with 200 g. of ice. 1,2-diphenyl-4-(l'- N-t-butylcarbamyl-l-methyl) ethylpyrazolidin-3,5-dione is obtained, melting at 164l65 degrees C. Elemental analysis agrees with the calculated value.

The same compound is obtained if 6 ml. of cold, liquid isobutylene is substituted for the tert.-butyl alcohol and the procedure is repeated this time employing a pressure vessel.

EXAMPLE IX Following the procedures of the appropriate preceding Examples V, VI, VII, or VIII, the following additional substituted-carbamylpyrazolidin-3,S-diones tabulated below are prepared from the appropriate nitriies of Example II.

methyl methyl methyl methyl methyl n-propyl methyl methyl l-propyl methyl methyl n-butyl methyl methyl l-butyl methyl methyl see-butyl ethyl methyl hydrogen ethyl methyl methyl ethyl methyl ethyl ethyl methyl n-propyl ethyl methyl n-butyl ethyl methyl i butyl ethyl methyl i-propyl ethyl methyl t-butyl ethyl methyl n-amyl ethyl methyl t-amyl n-propyl methyl hydrogen n-propyl methyl methyl n-propyl methyl ethyl n-propyl methyl u-propyl npropyl methyl n-hutyl n-propyl methyl l-butyl n-propyl methyl 1-propyl phenyl methyl ydrogen phenyl methyl methyl phenyl methyl ethyl phenyl methyl n-propyl phenyl methyl n-butyl phenyl methyl l-bntyl phenyl methyl r-prop l -(CIIz)4 methyl 2 4- th yl (CH2)4 n-propyl 2)4 n-butyl (CH2) 4 l3-butyl 2)4- l-propyl H2)5 methyl 2)5 ethyl (OH2)an-propyl 2)s P Hz) s l-Dropyl z)5 l-butyl H2)u hydrogen (CHz)emethyl (CH2)5 ethyl (CH) u n-propyl '(CH:2)g n-butyl (CI-I2)G t-butyl CH2) -butyl 2) 0- "P PZV -CH' 1CH(CH3) CHzCHzmethyl CH2OH(CH3) CHzCH2 etnyl CHZCH(CH CHzCHg n-propyl CI-I2OH(CH CH2OI-I2- n-butyl CHQCH(CH3) CHzC Hgt-butyl -CHzCH(CHa)CHzCHzl-butyl CH2CH(CH3) CH2CH2 l-propyl CHgCHzCH(CH3)CHzCHzmethyl -CI-I2CH2CH(CHa)CHzCHz ethyl -CHZCH CH(CH )CH2CH2- n-propyl -CHzCH2OH(OH3)CHzCH2 n-butyl OHgCH2CH(CH3)CH2CHz t-butyl -CH CI-I CH(CH3) CHzCHzi-butyl -CH;CH(C2H5) CH2CH2 hydrogen -CHzCHgCH(C2H5) CH2CHQ- hydrogen CHzCH2NH CH2CH2 hydrogen CHzN (C2115) CH2CHZCHE' hydrogen 10 EXAMPLE x Preparation of 1-(p-hydroxyphenyl)-2-phenyl 4-(1'-carbamyl) cyclohexylpyraz0lidin-3,5-di0ne The procedure of Example V is followed substituting the 1- (p-hydroxyphenyl -2-phenyl-4-( 1'-cyano) cyclohexylpyrazolidin-3,5-dione of Example III for the corresponding nitrile. The crystalline product has an elemental analysis corresponding to the calculated values.

EXAMPLE XI Following the applicable procedures of Example V or of Examples VII and VIII, the carbamyl-pyrazolidin- 3,5-diones tabulated below are prepared from the appropriate nitriles of Example IV.

0 pHOCaH4-NO\H R -R 1 C H N-G JIONHR:

methyl methyl hydrogen ethyl methyl hydrogen n-butyl methyl hydrogen CH2CH2C H2CHzhydrogen -CHzCH(CH3)CHzCH2 hydrogen CH:CH(CH3) CH2CHzCH2- hydrogen 'OH2CH2OH(CH3)CHQOH2 i-propyl -C}I2CI'I(CH3)CH2CH2C 2- hydrogen OIIzCH(CH3)CHzOHzCI-I2 methyl -CH2CH(CH )OH2OH2CH; ethyl -CHzCH(OH3)CH2CHzCHzn-propyl CHzCH(CH3)CH CHzOH2 n-butyl -CH2CH(CH3)CH2CH2CH2 t-butyl CHgCH(CHa)CH2CH2CHzi-butyl -CHZCH(GH3)GHZCHZCH2 l-propyl o-hydroxyphenyl methyl hydrogen p-hydroxyphenyl methyl hydrogen o-methoxyphenyl ethyl methyl CH2CH2N (C 13)CH2CH2- hydrogen p-methylphenyl methyl hydrogen 2-pyridyl ethyl hydrogen l-propyl methyl hydrogen n-butyl methyl methyl i-butyl methyl ethyl s butyl methyl n-propyl 2-thienyl methyl hydrogen 5 -thiazolyl methyl hydrogen m-propylphenyl methyl hydrogen p-arnylphenyl methyl hydrogen p-methylmercaptoethyl hydrogen phenyl. m-amylmercaptomethyl hydrogen phenyl. p-propoxyphenyl methyl hydrogen CH;GH;CH(CH3)OH2OH; hydrogen CHCH2CH2OHzCHaCHrhydrogen phenyl ethyl hydrogen p-hydroxyphenyl ethyl methyl p-methoxyphenyl methyl ethyl 2-thiazolyl methyl n-propyl 2-pyridyl methyl n-butyl lpropyl methyl l-butyl 3 -thienyl ethyl t-butyl ethyl methyl n-amyl p-methyphenyl ethyl s-butyl CHzN(CH3)CH2CH2CHzhydrogen EXAMPLE XII The sodium salt of 1,2-diphenyl-4-(1'-carbamyl-lmethyl)ethylpyrazolidin-3,S-dione is prepared by treating a solution of the product of Example V in dimethoxyethane with an equivalent proportion of aqueous sodium hydroxide and evaporating ofl? the solvents. In similar fashion other salts, including the potassium, calcium, magnesium, lithium, strontium, ammonium and ethanolammonium salts are prepared from the products of the previous examples. In the case of the most soluble salts the reaction mixture is lyophilized and the residue purifled by washing with a little cold alcohol. The less soluble salts are recovered by filtration, preceded by partial evaporation where required.

11 What is claimed is: 1. A compound selected from the group consisting of those of the formula:

(il-R1 Iheny1-NO Ol IHR O and the pharmaceutically-acceptable salts thereof, wherein R is selected from the group consisting of phenyl and parahydroxyphenyl;

R when taken separately is selected from the group consisting of pyridyl, thienyl, thiazolyl, phenyl, hydroxyphenyl, alkoxyphenyl, said alkoxy group having up to 3 carbon atoms, alkylphenyl and alkyl mercaptophenyl, said alkyl groups having up to carbon atoms,

R when taken separately is selected from the group consisting of methyl and ethyl, provided that R is methyl when R is alkyl,

R and R when taken together with the quaternary carbon atom to which they are attached form a cyclic substituent selected from the group consisting of cyclobutyl, cyclopentyl, monoalkyl cyclopentyl, cyclohexyl, monoalkyl cyclohexyl, cycloheptyl, piperidyl, and N-alkyl piperidyl, each of said substituents having up to two carbon atoms,

and R is selected from the group consisting of hydrogen and alkyl of up to five carbon atoms.

2. A compound of the formula:

wherein R is phenyl; wherein R is alkyl of up to five carbon atoms; and wherein n is an integer of from 3 to 6.

3. 1,2 diphenyl 4-(1-carbamyl)cyclohexylpyrazolidin-3,5-dione.

4. 1,2 diphenyl 4 (1'-carbamyl)cyclopent'ylpyrazolidin-3,5-dione.

5. 1,2 diphenyl-4-(1-N-i-propylcarbamyl)cyclohexylpyrazolidin-3,5-dione.

6. 1,2 diphenyl 4-(1-N-t-butylcarbamyl)cyclohexylpyrazolidin-3,S-dione.

7. A compound of the formula:

Phenyl-N-O O O NHR;

References Cited by the Examiner UNITED STATES PATENTS 2,700,670 1/55 Hafiiger 260-310 I FOREIGN PATENTS 1,048,710 8/ 53 France.

1,263,770 5/61 France. 1

811,700 4/59 Great Britain. I 5 854,950 11/60 Great Britain.

OTHER REFERENCES Luria et al.: Chem. Abstracts, vol. 53, col. 18007 (1959).

IRVING MARCUS, Primary Examiner.

DUVAL T. MCCUTCHEN, NICHOLAS S. RIZZO,

Examiners. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE OF THE FORMULA: 